Some experts said the OraQuick test’s $40 price would prevent many people from using it to screen partners. (Ángel Franco/The New York Times )

Published: October 5, 2012

The first rapid home-testing kit for H.I.V. has just gone on sale for $40, marketed as a way for people to find out privately if they have the virus that causes AIDS.

But some experts and advocates say that another use, unadvertised, for the OraQuick test — to screen potential sexual partners — may become equally popular and even help slow an epidemic stuck at 50,000 new infections each year in the United States.

There are reasons to think that screening might make a difference. Studies have found that a significant minority of people who are H.I.V.-positive either lie about their status or keep it secret, infecting unsuspecting partners.

And though the manufacturer, OraSure Technologies, is not promoting the use of the test for screening, 70 percent of the 4,000 men and women in the company’s clinical trials said they would either definitely or very likely use it that way. Some even suggested that the company sell boxes of two so couples could be tested together.

The only study of the practice — a small one involving 27 gay men who frequently had sex with virtual strangers without using condoms — found that it probably prevented some infections. The study was published online in August by the journal AIDS and Behavior.

“If it becomes a community norm, people may start testing their partners,” said Alex Carballo-Diéguez, the lead author of the study, who is a psychology professor at Columbia University and the associate director of the H.I.V. Center for Clinical and Behavioral Studies at the New York State Psychiatric Institute. “On sex sites now, men advertise themselves as ‘drug-and-disease-free.’ They could start saying ‘D-and-D-free, and willing to prove it.’ ”

Other AIDS experts had doubts. Some thought $40 was too much for people who need to screen multiple partners. Others said that men and women who are not comfortable demanding that their partners wear condoms would be unable to insist on a test.

And some, including Anthony S. Fauci, the country’s best-known AIDS doctor, worried that a negative test could lead partners to forgo condoms, removing the barrier to both H.I.V. and other diseases like gonorrhea.

The OraQuick test is imperfect. It is nearly 100 percent accurate when it indicates that someone is not infected and, in fact, is not. But it is only about 93 percent accurate when it says that someone is not infected and the person actually does have the virus, though the body is not yet producing the antibodies that the test detects.

The men in Dr. Carballo-Diéguez’s study were given 16 tests each and followed for three months. None of them had unprotected sex with anyone who tested positive.

Of the 101 partners they tested, 10 were positive. In six cases, it was how the partner first learned he was infected. (Ten percent is a very high success rate for H.I.V. testing, experts said.)

Twenty-three other partners refused testing. Two, after being asked, admitted knowing they were infected.

Seven men got angry, and one stomped on the kit. One man walked out saying he wanted to be alone and broke off contact.

Asking usually did not ruin the moment’s intimacy, the men said. Some pairs did the tests together, swabbing each other’s gums. Some passed the 20-minute wait talking, playing video games or in foreplay. One 47-year-old man found the wait helpful, telling the researchers, “It gives you that extra 20 minutes to decide, ‘O.K., if this comes back negative, am I really ready to bareback?’ ” — slang for having sex without a condom.

Dr. Carballo-Diéguez said people’s decision about whether to screen would depend on various factors, including the test’s price and how comfortable they were with its imperfect accuracy.

OraSure appears ambivalent about partner screening. AIDS experts said the company might fear lawsuits by people infected by partners who got false negatives — a possibility it declined to comment on. In an interview, its president, Douglas A. Michel, said, “We’re supportive, as long as it’s between consenting adults.”

But he also said the label would warn that the test “should not be used to make decisions that might put the user at risk of contracting H.I.V.”

Asked about the price of the test, he said market research indicated that most users would buy it once or twice a year, so $40 was “appropriate.”

The technology is similar to that in home pregnancy kits, which sell for as little as $4 each.

Larry Kramer, the longtime AIDS activist, called screening “a potentially cool idea, but it depends on how the partner/date/trick/stranger takes it.”

If a test had been around 30 years ago, he added, “there would have been a lot more people alive today.”

Hunteur Vreeland, a professional party organizer who arranges “gay porn harbor cruises” and “underwear erotic parties” at Paddles, a dungeon-themed club in New York, said he would even consider selling home tests at his events. He now offers free H.I.V. testing at them in conjunction with the Men’s Sexual Health Project of Bellevue Hospital Center.

“Knowledge is never a bad thing,” he said. He added that if a potential partner unexpectedly pulled out a test kit, “I’d probably say — ‘hey, jackass, if I wanted to know my status, I’d find it out myself,’ and I’d leave.”

Then he reconsidered.

“But if the dude was hot, and maybe I was on the cusp of getting tested anyway — well, then, maybe I’d be, ‘All right, I’ll take it.’ ”

Justin Goforth, the director of medical adherence for Whitman-Walker Health, a clinic in Washington with many AIDS patients, said he doubted that screening would help his clientele.

“It’s expensive,” he said. “People who can afford it already have strategies for avoiding infection. It won’t help women whose men refuse to use condoms, because he’ll refuse to take the test, too. And the same for young black men — they usually get infected by older men, and the power dynamic is not in their favor.”

“Nobody should take this test and 20 minutes later go have unprotected sex,” he said. “The art of talking to a partner is the primary thing. You have to respect each other and tell the truth.”

But numerous studies have shown that many sexual partners do not.

In a large 2007 survey led by Dr. Robert Klitzman, also of Columbia University and the New York State Psychiatric Institute, nearly 20 percent of infected gay men admitted to having had unprotected sex with at least one partner without revealing their status.

Men made many excuses, saying they believed that they were not infectious or felt it was the partner’s duty to ask.

An equally large 2003 study led by Dr. Daniel H. Ciccarone of the University of California, San Francisco, found that about 9 percent of H.I.V.-positive heterosexual men and women and about 14 percent of infected gay or bisexual men had recently had unprotected sex with someone they either knew was uninfected or were unsure about, without revealing their own infection.

The authors estimated that in the six months their study covered, 17,000 infected gay men across the country and almost 5,000 infected heterosexual men and women had sex without telling the truth.

Among study participants with the same end-of-study response status, HCV RNA declines at 4 weeks were similar between treatment-naive patients and treatment-experienced ones.

Participants in treatment studies of hepatitis C virus (HCV) infection are generally categorized as treatment naive or treatment experienced, based on previous receipt of an interferon-based regimen such as pegylated interferon-α plus ribavirin (P/R). Treatment-experienced individuals with P/R treatment failure can be further subdivided into relapsers, partial responders, and null responders, based on plasma HCV RNA concentrations during and after therapy.

To date, no data have emerged to indicate resistance to interferon-α–based therapy, suggesting that the response rate to P/R should not be lower with retreatment than with initial therapy. To examine this issue, investigators at the FDA examined data for participants in eight earlier trials (2996 treatment-naive and 754 treatment-experienced patients with genotype-1 HCV infection who had completed P/R treatment and had week-4 viral load data available).

In both treatment-naive and treatment-experienced patients, the HCV RNA change from baseline at 4 weeks was strongly correlated with the likelihood of achieving a sustained viral response (i.e., an undetectable viral load 24 weeks after the end of treatment). When therapy response was compared between treatment-experienced patients (stratified according to previous treatment outcomes) and treatment-naive patients (stratified based on end-of-treatment outcomes), the 4-week decline in HCV RNA was similar between the corresponding groups.

Comment: Despite its retrospective nature, this study suggests that responsiveness to P/R does not decrease with retreatment. As the authors point out, this finding has implications for trials of interferon-based triple therapy — P/R plus one of the newer direct-acting antivirals emerging for HCV.

Chronic hepatitis B and chronic hepatitis C virus infections are both potentially fatal conditions, but few head-to-head comparisons of clinical outcomes have been attempted.

Among almost 7000 American men included in a large prospective database of men who have sex with men, about 5% of participants entered the study with each type of chronic hepatitis. After a median follow-up of almost 8 years, all-cause mortality was similar in both groups, but liver-related mortality was significantly higher for those with chronic hepatitis B infections. This finding held true for both HIV-negative and HIV-positive participants, including those who were severely immunocompromised.

Excluding the few men in the study who underwent treatment for hepatitis C infection did not change the pattern. However, liver-related mortality among participants who were coinfected with hepatitis B and HIV and who were enrolled after 2002 was markedly lower than among those who were enrolled earlier, possibly reflecting use of newer antiviral drugs that are active against both HIV and hepatitis B virus.

Comment: This study is the first in which the effects of hepatitis B and hepatitis C virus infections were compared in a relatively homogeneous population. Its results are worth noting because a surge of public health advertisements have brought hepatitis C screening and treatment into the public eye recently. Clinicians should remember that, despite vaccination, hepatitis B is still out there, and effective oral treatment can save lives.

A new model that includes alpha-fetoprotein level predicts 5-year recurrence of posttransplant HCC better than the standard Milan criteria.

Liver transplantation is the best treatment option for early stages of hepatocellular carcinoma (HCC). Currently, the Milan criteria are used to identify transplantation-eligible patients with a low risk (10%–15%) for posttransplantation tumor recurrence. However, recent evidence has raised concern that these criteria might be too restrictive.

Using data from a cohort of 537 patients in France who received a liver transplant for HCC, researchers developed a new predictive model that included alpha-fetoprotein (AFP) level. This AFP model was then validated in a separate cohort of 435 liver transplant recipients with HCC who were part of a national transplantation program in France and were followed prospectively.

Regression analysis showed that the number of tumors, tumor size, and AFP level were independent predictors of 5-year tumor recurrence (the primary endpoint). Three combinations of these variables defined patients as low risk:

One to three nodules with maximum tumor diameter <3 cm and AFP 1000 ng/mL

One to three nodules with maximum tumor diameter 3 to 6 cm and AFP 100 ng/mL

More than four nodules with maximum tumor diameter <3 cm and AFP 100 ng/mL

In a simplified model, researchers transformed Beta coefficients of variables from the regression model into points, adding these to obtain a score. A score of 2 was the cutoff for low versus high risk. In the validation cohort, a score >2 (vs. 2) was associated with a higher 5-year recurrence rate (50.6% vs. 8.8%, P<0.001) and a lower 5-year survival rate (47.5% vs. 67.8%, P=0.002). The AFP model was superior to the Milan criteria in predictive performance based on a comparison of predicted and observed recurrence events with each. Some patients identified by the AFP model as low risk (e.g., patients with AFP 100 ng/mL) did not meet Milan criteria, and some identified as high risk (e.g., patients with AFP >1000 ng/mL) did meet the Milan criteria.

Comment: These new selection criteria identified not only transplantation candidates with low risk for HCC recurrence who would have been excluded using the standard Milan criteria, but also those at high risk for HCC recurrence who would have been eligible under those criteria. With the rise in the number of patients with HCC listed for transplantation, continual refinement of the selection criteria is critical. This AFP model could be the next iteration of those criteria.

Patients with HIV and HCV were prone to hepatic steatosis that frequently progressed over time in a recent study.

In the retrospective study, researchers evaluated 146 patients coinfected with HIV and HCV who underwent two biopsies separated by 1 year or more (median 3.3 years). The presence and progression of hepatic steatosis (HS) was monitored within the cohort.

HS was present in 87 patients at the initial biopsy and 113 in the subsequent biopsy (P<.001), with progression detected in 60 participants, including eight who progressed by two or more grades. Eleven participants regressed by one or more grades between biopsies. Change to fasting plasma glucose (OR=1.4; 95% CI, 1.04-1.9 per 10 mg/dL increase) and cumulative dideoxynucleoside analog use (OR=1.5; 95% CI, 1.2-1.8 per year exposed) were associated with HS progression via multivariate analysis.

Liver fibrosis stages were present in the cohort at the following rates (P=.019 for change):

Stage 0: 20% of patients at initial biopsy, 12% at second

Stage 1: 34% at initial biopsy, 27% at second

Stage 2: 19% at initial biopsy, 29% at second

Stage 3: 21% at initial biopsy, 16% at second

Stage 4: 7.5% at initial biopsy, 16% at second

Progression of one or more fibrotic stages was associated with persistent or onset of steatohepatitis (OR=2.4; 95% CI, 1.01-5.7). At initial biopsy, 24 participants had steatohepatitis, which increased to 27 at the follow-up (P=.602 for difference), including nine persistent cases and 18 patients who progressed to steatohepatitis. Median NAS score increased from 3 to 4 between biopsies (P=.002); 65 participants experienced an increase and 35 a decrease.

“HS is frequently detected in HIV/HCV-coinfected patients with and without [antiretroviral therapy], and high rates of progression to severe HS are observed in them,” the researchers concluded. “This is a major concern, given that among individuals with HS, those with features of steatohepatitis are at increased risk of fibrosis progression. … The natural history of HS and steatohepatitis in HIV/HCV coinfection needs further investigation, particularly in patients receiving the newer antiretroviral drugs.”

Injection drug users with HCV were found at increased risk for death from all causes up to 30 years after HCV transmission, with greater risk for liver-related death according to age, in a recent study.

Researchers evaluated 523 anti-HCV-positive injection drug users (IDUs) with stored, frozen sera who had been admitted for resident drug abuse treatment between 1970 and 1984 at a Norwegian medical facility, for a mean 33 years of observation. Mortality due to liver-related or other causes was compared between patients who were HCV RNA positive (n=328) and negative (n=195).

During follow-up, 220 patients died. The mortality rate associated with all causes was 1.85 (1.62-2.11) per 100 person-years for the entire cohort, with a higher rate for males than females (2.11, 1.84-2.46 vs. 1.39, 1.07-1.79). Among RNA-positive patients, the mortality rate was 1.75 (1.47-2.07) compared with 2.05 (1.66-2.54) for RNA-negative patients (P=.248 for difference) (95% CI for all).

Common causes of death across the entire cohort included drug or alcohol intoxication (49.5%), suicide (9.1%) and accident (8.2%), with no significant differences between groups in terms of cause distribution (P=.598). Among HCV RNA-positive patients, 7.5% of deaths were due to liver disease, with a rate for deaths related to HCV of 0.09 per 100 person-years (95% CI, 0.05-0.16).

Of 17 RNA-positive patients aged 50 and 60 years who died, five were attributed to liver disease. Mortality incidence due to liver-related issues increased with age, with a cumulative rate of 0.07 (0.03-0.17) per 100 person-years for patients aged 49 years and younger and 0.91 (0.38-2.18) for patients aged 50 years and older (95% CI for both).

“The present study, on one hand, illustrates the high mortality rate among IDUs from drug-related causes,” the researchers wrote. “On the other hand, it shows increased morbidity and mortality due to HCV with increasing age and time since HCV transmission. This may be moderated by increased antiviral treatment. In the long term, serious HCV-related liver disease could be reduced through decreased intravenous drug use, more intensive prevention of syringe sharing among IDUs, and consequently, reduced transmission of viral hepatitis.”

Abstract and Introduction

Abstract

The combination of pegylated interferon (Peg-IFN) and ribavirin is currently the gold standard therapy in patients with HCV chronic infection. The duration of therapy, as well as the therapeutic dosage, depend on the genotype. Identification of the genotype and rapid virological response (RVR) are widely accepted as the most important predictors of clinical outcome during antiviral therapy but to optimize cost-benefits and to reduce possible side effects, further prognostic factors are needed. Squamous cell carcinoma antigens immunocomplex (SCCA-IC) has been reported to be increased in the serum of patients with liver cancer. In this multicentric prospective study, we investigated the serum levels of SCCA-IC in 103 patients with HCV chronic infection. Serum HCV-RNA was detected before the beginning of treatment, after 4, 12, 24 or 48 weeks, and at week 24 during follow-up. RVR, early virological response and sustained virological response (SVR) were assessed following the international guidelines. SCCA-IC levels were higher in responders (238 AU, interquartile difference 130–556 AU) and decreased significantly to 125 AU (70–290 AU). The mean baseline value in nonresponders was 149 AU (86.5–306.5 AU), but after 4 weeks of treatment the serum levels decreased to 115 AU (80–280 AU): the profile of reduction was different between patients with or without a positive SVR. Logistic regression with SVR as dependent variable identified as significant independent variables: the reduction in SCCA-IC after 1 month (OR = 4.82; 95% CI 1.39–16.67; P = 0.131) and a genotype other than 1 (OR = 0.094; 95% CI 0.21–0.42; P = 0.002); sex and age were also significant factors influencing SVR. SCCA-IC seems to be a reliable independent prognostic marker of therapeutic effectiveness in anti-HCV positive patients undergoing antiviral therapy.

Introduction

The gold standard treatment for chronic hepatitis C, to prevent or delay progression to liver cirrhosis and hepatocellular carcinoma (HCC), is currently the combination of pegylated interferon-α (Peg-IFN-α) with ribavirin.[1,2] The HCV genotype and a rapid virological response (RVR) have been widely recognized as the two most important prognostic factors for the response to antiviral therapy.[3,4] The international guidelines for the treatment of HCV patients have suggested that these prognostic factors may be usefully applied to tailor the therapeutic regimen and optimize the cost-benefit ratio.[5] Nevertheless, additional prognostic factors are urgently needed in clinical practice.

Recently, in a preliminary study, it was reported that serum levels of squamous cell carcinoma antigen immuno-complex (SCCA-IC) were decreased in patients with HCV-related cirrhosis who responded to antiviral therapy.[6] However, the limited number of patients so far investigated, and the lack of studies in patients with chronic HCV-related hepatitis do not allow definite conclusions to be drawn as regards the validity of this test in patients undergoing antiviral therapy. In particular, there are no data available correlating the use of SCCA-IC with RVR, widely recognized as the gold standard marker of clinical response to antiviral therapy.

SCCA-IC is an immuno-complex whereby IgM immunoglobulins link the serin inhibitor protease SCCA.[7,8] SCCA was first reported to be expressed in the liver of HCC patients and for this reason, was proposed as a potential biomarker for the detection of HCC.[9] SCCA-IC serum levels have been demonstrated to show a better diagnostic capacity than SCCA and have therefore been proposed for use in combination with alpha-fetoprotein as an additional biomarker for HCC detection.[10]

Aim of this study was to test the utility of SCCA-IC as a marker of response in patients with HCV chronic infection undergoing antiviral therapy. A multicentric prospective study was designed, in which serum samples were collected at baseline before starting the therapy, at RVR, early virological response (EVR) and 6 months after the end of therapy, and a cohort of patients with HCV chronic infection undergoing antiviral therapy were enrolled.

Materials and Methods

Patients

During the period 2007–2010, 103 patients referred to the following centres: Unit of Internal Medicine 'C. Frugoni' and of Infectious Diseases, University of Bari; Unit of Gastroenterology, University of Pisa; and Unit of Gastroentorology, University of Modena And Reggio Emilia were enrolled in this study.

Study Design

In total, 103 patients were recruited, 61 men and 42 women. Mean age was 53.4 year (±12.7 year) in men and 58 year (±9.5 year) in women, with a significant difference between the two groups (t-test = 2.05; P = 0.04).

Blood samples were collected at baseline before the beginning of therapy, after 4, 12, 24 and 48 weeks during treatment and at 24 weeks of follow-up. The study was not supported by any pharmaceutical company. Informed consent was obtained from all patients.

Patients were treated with weekly subcutaneous pegylated interferon (Peg-IFN)-α2a (180 μg/week) or Peg-IFN-α2b (1.5 μg/kg/week) plus oral ribavirin at a dosage of 800–1200 mg/day depending on pretreatment body weight (800 mg/day for weight <60 kg, 1000 mg/day for weight ≥ kg and <75 kg; and 1200 mg/day for weight ≥75 kg). This study was not randomized, and the physicians in charge of the patients chose the Peg-IFN at their own discretion. Patients with genotype 2 and 3 were treated for 24 weeks, and those with genotype 1 and 4 for 48 weeks. Virological response was evaluated at weeks 4, 12, 24 and 48 during treatment and at 24 weeks of follow-up by qualitative PCR (Amplicor; Roche Diagnostic System, France), with a sensitivity of 50 UI/mL. HCV genotype was determined before treatment in all patients with the INNO-LiPA HCV II kit (Bayer Diagnostics, Emeryville, CA, USA). Sustained virological response (SVR) was defined as the absence of detectable HCV-RNA in serum by qualitative PCR at the end of therapy and at week 24 of follow-up. Early virological response was defined as undetectable serum HCV-RNA or a reduction in HCV-RNA levels by at least 2 logs from baseline values at week 12 of treatment. Rapid virological response, was defined as undetectable serum HCV-RNA at week 4 of treatment. Patients with measurable HCV-RNA by qualitative PCR at the end of the follow-up period were considered nonresponders.

SCCA-IC Measurement

SCCA-IC serum concentrations were determined in sera previously collected and stored at −20 °C until use. Serum concentrations of SCCA-IC were measured as in our previous works, using ELISA commercial kits purchased from Xeptagen (Padua, Italy).

Statistical Analysis

Categorical variables are summarized as count and percentage. Chi-squared test was used to evaluate differences between independent groups. Comparisons were made by parametric tests if normally (Gaussian) distributed, nonparametric tests otherwise. Quantitative variables are summarized as mean and standard deviation. Differences of SCCA-IC, lacking a Gaussian distribution, are summarized as median and interquartile range and comparison was performed by Kruskal–Wallis for comparing multiple independent groups or Friedman test for nonparametric repeated measure analysis of variance. Multiple comparisons between paired or independent groups were performed using Wilcoxon test and P-values were adjusted taking into account the number of comparisons according Bonferroni.

The percentage variation, determined as the ratio between the difference of SCCA-IC at time t0 less SCCA-IC at time t-1, divided by SCCA-IC at time t-1, was calculated to evaluate the reduction in SCCA-IC concentrations between two consecutive time points. The percentage variation was then classified in two classes according to the median value. A logistic regression model was built to evaluate the effect on SVR of the class of SCCA-IC reduction (more than 12% after the first month and after the third month, more than 7% at the last follow-up visit), genotype (1 vs other), adjusted for age (classified as <58 vs≥58 year) and sex (M vs F).

To evaluate the concordance of percentage of SVR patient predicted by SCCAIC classes and prediction of SVR by RVR and EVR was performed the McNemar test to compare paired percentage. A P-value <0.05 was considered statistically significant. All analyses were performed with software SAS 9.2 for PC (SAS Institute, Cary, NC, USA).

Results

There were 63 responders (Table 1); mean age was 53.5 year (±11.9 year) for responders and 58.3 year (±10.7 year) for nonresponders; this difference resulted statistically significant (t-test = 2.1; P = 0.038) (Fig. 1). There were no statistically significant differences in the percentage of responders between men and women: 62.3% (38/61) vs 59.5% (25/42) (χ2 = 0.08; P = 0.7767).

Figure 1. Patients course from the study start to the end of follow-up.

Genotype 1 was observed in 41.3% (26/63) of responders, vs 90% (36/40) of non responders: the percentage of genotype 1 was significantly different between responders and nonresponders (χ2 = 24.24; P < 0.0001). The median value of SCCA-IC by genotype and response is shown in Table 2 and profile by time of genotype 1 patients is shown in Fig. 2. Responders with all genotypes had higher levels of SCCA-IC than nonresponders. Furthermore, in responders, the level of SCCA-IC showed a tendency to decrease, whereas in nonresponders the SCCA-IC level appeared to remain the same at each time point. The median level of SCCA-IC at baseline resulted lower respect to overall median value, but profile for responders patients resulted similar (like a parallel line) until the last determination, where values for genotype 1 and overall sample resulted the same. Nonresponders patients with genotype 1 had identical value respect to overall sample, because the most part of nonresponders patients was genotype 1.

Figure 2. Median and interquartile range of SCCA-IC concentrations at each follow-up time point. In responders, the median level at each time point was less than the median at the previous time, while in nonresponders the median level was approximatively the same at each time point.

The initial value of SCCA-IC (Fig. 2) in responders was 238 AU (130–556), this decreased to 188 AU (116–400) after 1 month, to 134 AU (90–385) after 3 months and reached the value 125 AU (70–290) at the end of follow-up. In nonresponders, the initial value was 149 AU (86.5–306.5) and remained substantially unchanged after 1 month, 142.5 AU (82.5–286.5), showing a slight decrease after 3 months 115 AU (80–280) and remaining at this level until the end of follow-up: 119 AU (82–260). The difference in concentration between responders and nonresponders at the first month resulted statistically significant (P = 0.0031), while at the other time points it was not significant (P > 0.05). The decrease between consecutive time points resulted statistically significant (P < 0.001) in the responders group: the baseline-first month difference was 43 AU (15–101); first – third month, 38 AU (10–68); third month – end of the study, 14 AU (3–45). In the nonresponders group, the decrease at consecutive time points resulted significant between baseline-first month (5 AU; 0–14.5; P < 0.001), but not at subsequent time points, when the reduction was 0.5 AU (0–12.5) and 0 AU (9 to −8). Median reduction resulted significantly different between responders and nonresponders (P < 0.0001 at each comparison) at every time point. These results allowed us to conclude that the profile of reduction was different between patients that would achieve a positive SVR as compared to nonresponders.

To evaluate the effect of SCCA-IC reduction in SVR, a logistic regression model was built with the presence of SVR as dependent variable, while the independent variables were the class of SCCA-IC reduction after 1, 3 months and at the end of follow-up, genotype 1 vs others, sex (M vs F) and age (<58 vs≥58). The model resulted statistically significant (Table 3; P < 0.0001). Sex was not shown to be a statistically significant variable, while age younger than 58 increased the probability of achieving SVR (OR = 9.66; CI95% 2.21–42.15; P = 0.0025). An OR = 0.094 (CI95% 0.21–0.42; P = 0.002) was shown for genotype 1, suggesting that with this genotype patients are more likely to be nonresponders. Predictive factors of SVR were the reduction after first month, after the third month and at follow-up. No effect of interaction between time points and genotype resulted statistically significant, and this parameter was therefore removed from the model. Looking at the odds ratio, it seems that a reduction of more than 12% between the baseline value and the first time point increases by 4.82-fold the probability of SVR (95% CI 1.39–16.67; P = 0.131). A reduction between the first month and third month of more than 12% increases the probability of SVR 15-fold (3.44–66.74; P = 0.0003), and a further reduction of more than 7% until the end of the study period increases the probability of SVR 9-fold (95% CI 2.22–42.15; P = 0.043).

Figure 3 shows the probability of response for each value of percentage reduction in SCCA-IC between baseline and the first month for the whole sample and for genotype 1 subgroup: the probability of SVR obtained with the univariate logistic model (independent variable SVR Y/N and dependent percentage reduction in SCCA-IC as continuous variable) is increased by more than 50% for small levels of reduction starting from 7% to 8% as compared to the baseline value. For genotype 1, subgroup instead the probability of being a responder patient at the end of follow-up resulted more than 50% for higher value of reduction (at least 15%). Positive predictive value of SVR of SCCA-IC reduction was 69.8% (44 with reduction/63 SVR patients), while RVR 79.4% (50 RVR/63 SVR) and EVR 96.8% (61 EVR/63 SVR). There was a statistically significant difference between predictive value of class of SCCA-IC and EVR (McNemar test 17.0, P < 0.0001), but not respect to RVR (McNemar test 1.8, P = 0.179). This results are confirmed in the subgroup of genotype 1 patients: predictive value of class of SCCA-IC reduction was 65.4% (17 with reduction/26 SVR), while for RVR was 69.3% (18/26), that resulted not significantly different (P = 0.76) and for EVR 96.1% (25/26) significantly different respect to class of SCCA-IC (P = 0.0047) (Table 4).

Figure 3. Probability of being a responder as a function of the SCCA-IC reduction. The x-axis shows the percentage variation obtained as SCCA-IC value at baseline less the value at the first month divided by the baseline value.

Discussion

In this study, we have demonstrated that a decreased serum concentration of SCCA-IC after 4 weeks of antiviral therapy is an independent prognostic factor of therapeutic response. We base this conclusion on the following data: (i) the reduction in SCCA-IC was significantly different between patients achieving SVR or not; (ii) the profile of SCCA-IC is different between responders and nonresponders even with different genotypes; (iii) If the reduction is evaluated as percentage, the effect of the decrease between baseline and the first month value becomes even more noticeable.

The model evaluating the effect of predictors such as genotype and SCCA-IC reduction at each time point was shown to be well able to predict the response. The reduction at the first time point seems to be a good predictor with low variability, and the probability allows us to conclude that if a reduction is observed at the first follow-up visit the patient will achieve a positive clinical response.

The genotype shows a strong influence on obtaining a SVR, but does not affect the conclusions about SCCA-IC, that can therefore be considered a useful marker for monitoring patients when measured at each visit: before starting therapy and after the first and second follow-up visit. Thus, if SCCA-IC serum levels reduce during therapy, the patient will achieve SVR. Should be noticed that genotype 1 subgroup has less probability to be a responder, but even in this group if a reduction in SCCA-IC level is observed a SVR could be obtained.

In a previous work by Giannini et al.,[6] the authors reported that a higher SCCA-IC, but not SCCA, serum concentrations reduction in patients with liver cirrhosis was observed in responders to antiviral therapy. Probably because of the small sample size, they could not make an appropriate test of the significance of the reduction with respect to the future response. Moreover, in that work the genotype was not evaluated together with SCCA-IC in a multivariate model. In this article, instead, the authors focused on the definition of a parameter to predict SVR, so both genotype and repeated reductions of the marker have been evaluated in a multivariate model. This confirmed the importance of the reduction of the marker, more than the value of the marker itself, as an independent variable, specifically with respect to the genotype. Our data demonstrate that patients with SVR have a decreasing profile according to genotype. This suggests that SVR could be predicted by genotype, as already known, but that important information on a positive response can be gained if there is a reduction more than 12% at the first month as compared to the baseline value.

Therefore, an antigen immuno-complex such as SCCA-IC can predict the clinical outcome. It remains to be seen what molecular mechanism is related to the decrease in SCCA-IC, to explain its significance as a prognostic factor.

In other studies, SCCA-IC was reported as a new biomarker for early detection of HCC. However, while the sensitivity performance was very encouraging, the specificity was disappointing. In particular, patients without HCC but with underlying chronic liver disease had unexplainably high serum levels of SCCA-IC.[8,11] We hypothesize that SCCA-IC could be related to the liver fibrosis/inflammation status.[12] In fact, we detected increased levels of SCCA-IC in patients with systemic sclerosis (SS). In particular. among these patients, we found that those with fibrotic involvement of the lung displayed the highest serum levels of SCCA-IC, as compared with the other subsets of SS patients with a different clinical outcome.[13] Therefore, it is likely that SCCA-IC serum levels reflect the fibrosis-immunity-related status, which could explain why this parameter is a prognostic factor independently of the genotype or the RVR.

In conclusion, we report a new prognostic factor that can predict the therapeutic response in patients with chronic hepatitis C undergoing antiviral therapy. SCCA-IC can be easily measured using a commercially available ELISA kit. Finally, we suggest that being an independent prognostic factor, SCCA-IC may be useful to refine patients selection, discriminating those patients that will benefit from antiviral therapy and thus optimizing the cost-benefit ratio.

Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

Losing track of clinical trial participants prior to study completion is a common and serious problem in medical research that needs to be addressed, according to a National Research Council panel.

"The assumption that analysis methods can compensate for such missing data are not justified, so aspects of trial design that limit the likelihood of missing data should be an important objective," panel members led by Roderick J. Little, PhD, of the University of Michigan, wrote in the Oct. 4 issue of the New England Journal of Medicine.

Such common methods as the "last observation carried forward" to estimate outcomes in trial participants whose real outcomes are unknown rely on assumptions that are frequently false, the group argued.

Instead, Little and colleagues contended, trials should be designed more carefully to limit the incidence of missing trial data.

The panel began their work after the FDA asked the National Research Council in 2008 for advice on the question, as part of the regulator's plan to develop guidance for drug and device companies on clinical trial design.

Little and colleagues wrote a report in 2010, but because the issue remains relevant, they provided a new summary with policy recommendations in the current NEJM issue.

Patients who stop treatment in a study because of adverse effects, lack of efficacy, or other factors are one of the most common reasons data go missing, the researchers noted.

Frequently, study investigators fill the resulting data gaps with estimates of how the dropouts would have performed had they stayed in the trial.

Although that approach can have merit, the estimates "all require unverifiable assumptions," panel members wrote, and "there is no foolproof way to analyze data in the face of substantial amounts of missing data."

Instead of trying to replace missing data with estimates, a better approach would be to keep data from going missing in the first place. Little and colleagues recommended that study investigators work harder and smarter to retain participants in trials, including those who stop taking study treatments.

"The consensus of the panel was that in many studies, the benefits of collecting outcomes after participants have discontinued treatment outweigh the costs," they wrote.

Little and colleagues offered eight suggestions for designing trials to minimize missing data, and eight more related to the conduct of such trials.

Their ideas for trial design included the following:

Target populations not well served by current treatments

Begin studies with all participants receiving the active treatment, with only those tolerating and adhering to it going on to the randomized phase

Allow flexible treatment regimens to maximize efficacy and safety

Consider designs in which the study treatment is added to an existing active treatment

Keep follow-up periods short

Allow use of rescue medications

In long-term efficacy studies, use a randomized withdrawal design in which patients remaining on active treatment are re-randomized to stay on it or switch to placebo

Consider use of rescue medications or treatment discontinuation as an outcome measure

The group's suggestions for trial conduct were as follows:

Select trial investigators with an established history of good participant retention

Set targets for missing data and monitor them during the trial

Provide incentives (which may be financial) to investigators and participants for completeness of data collection

Minimize burdens on trial participants with respect to convenience and other factors

Provide continued access to effective treatments prior to regulatory approval

Assess participants for the likelihood of dropping out, and seek to alleviate factors that may impel them to drop out

Keep participant contact information up to date

In a separate paper appearing in the same issue of NEJM, a group of statistical reviewers for the journal, led by James H. Ware, PhD, of the Harvard School of Public Health in Boston (and including one of the NRC panel members), described a review of the NEJM's own policies on missing data.

Ware and colleagues promised that they would be more hard-nosed about manuscripts that use statistical methods to compensate for missing data.

For some methods, the group indicated, "we will require justifications that the assumptions required for the validity of those methods are reasonable."

And, "when the missing data are sufficiently extensive to raise questions about the robustness of the results to unverifiable assumptions, we may require authors to conduct sensitivity analyses."

Ware and colleagues added that they would expect plans for dealing with missing data to be included in trial protocols posted on internationally recognized clinical trial databases.

Injection drug users on opiate substitution treatment with methadone cut their risk of HIV infection by more than half, researchers reported.

In a systematic review and meta-analysis, people on methadone treatment had a 54% reduction in the risk of HIV compared with the usual incidence of the infection seen among injection drug users, according to Georgie MacArthur, BSc, of the University of Bristol in Bristol, England, and colleagues.

The estimated prevalence of HIV is about 40% among the world's roughly 16 million injection drug users, the researchers noted, and injection drug use has driven several recent HIV outbreaks in Europe.

A standard approach to treating addiction is opiate substitution with methadone or buprenorphine (Subutex) but there has been no quantitative estimate of the effect of substitution therapy on HIV transmission.

To help fill the gap, MacArthur and colleagues conducted a systematic review, looking for data on how opioid substitution affected HIV incidence.

All told, they found 12 published studies with data on the effect of substitution treatment on HIV transmission, and they obtained unpublished data from three other studies.

All of the 15 studies looked at methadone substitution, they reported.

For a meta-analysis, data from nine studies – from the U.S., Canada, the U.K., The Netherlands, Austria, Italy, Thailand, Puerto Rico, and China -- could be pooled, they found, including 819 new HIV infections over 23,608 person years of follow-up.

The analysis showed "strong evidence" of a benefit: the rate ratio was 0.46, with a 95% confidence interval from 0.32 to 0.67, which was significant at P<0.001.

MacArthur and colleagues cautioned, however, that there was heterogeneity between studies that "could not be explained by geographical region, site of recruitment, or the provision of incentives."

Not all of the studies adjusted for confounding factors, but analysis of a subset of six that did still suggested that methadone substitution was associated with a 40% reduction in HIV risk.

The researchers cautioned that all of the included studies were observational and subject to both selection and attrition bias.

"The extent to which the studies were representative of all people who inject drugs and are receiving opiate substitution treatment is unclear," they noted.

Despite such limitations, however, the findings are "strong quantitative evidence of an association between opiate substitution treatment and reduced risk of HIV transmission among people who inject drugs," they concluded.

The study is a bookend to an earlier systematic review that found that substitution treatment reduced activities associated with a high risk of HIV transmission, according to Linda Gowing, PhD, of the University of Adelaide in Adelaide, Australia.

Taken together, the two studies "provide strong evidence" that the treatment – at least with methadone -- cuts both high-risk behavior and the risk of acquiring HIV, Gowing argued in an accompanying editorial.

She cautioned that the benefits of substitution therapy are likely to be lost when treatment stops -- especially if the treatment is not voluntary -- or when patients relapse and resume injecting drugs.

Policymakers, she argued, should aim at "maximizing the proportion of injecting drug users in the treatment program and promoting their retention" in care.

The study had support from the Centre for the Development and Evaluation of Complex Interventions for Public Health Improvement, the British Heart Foundation, Cancer Research UK, the Economic and Social Research Council, the Medical Research Council, the Welsh Assembly Government and the Wellcome Trust.

Many doctors are missing the signs that patients could be infected with HIV, researchers said after they found that one in four people with the disease could have been diagnosed at an earlier stage.

The British HIV Association (BHIVA), the body that represents HIV care professionals, said that patients with HIV are being denied longer life expectancies because they are being diagnosed too late.

A quarter of patients missed an opportunity for their HIV infection to be detected earlier because they were not offered a HIV test, according to BHIVA's audit of HIV testing and diagnosis in the UK.

Researchers said late diagnosis of the condition is a growing problem.

People who are diagnosed with more advanced HIV have a tenfold increased risk of death in the first year compared to those diagnosed with earlier stages of infection, they said.

The author of the report, Dr Ed Ong said: "Our data shows one in four people living with HIV could have had their condition diagnosed earlier.

"This is a serious wake-up call, and shows we need a pro-active and widespread testing programme which is tailored to those people who are most at risk."

BHIVA chair Professor Jane Anderson added: "Late diagnosis is the single biggest cause of death from HIV in the UK. It increases the risk of HIV related ill-health, of HIV being acquired by others, and significantly increases the costs of treatment.

"HIV is treatable, and if diagnosed in time, people with HIV can expect to have long and healthy lives. Sadly, opportunities for longer life expectancy for people with HIV are being thrown away by late diagnosis."

The research, which examined the records of more than 1,000 patients at HIV treatment centres in the UK, was published today in the Clinical Medicine Journal.

A baby with heart problems was infected with Hepatitis C on Thursday after a blood transfusion in a Gothenburg hospital.

“It’s extremely unfortunate and regrettable. A tragedy for the child and the parents,” said Mats Tullberg, chief physician of the Sahlgrenska University Hospital to the Göteborgs-Posten newspaper (GP).

The baby was undergoing a routine blood transfusion at the The Queen Silvia Children´s Hospital in Gothenburg, western Sweden, when the infection was noticed on Thursday afternoon.

The baby was then rushed to the Sahlgrenska hospital and the family was notified.

“The child and the parents are being taken care of at the hospital. They are getting support and the child is getting the necessary treatment,” he said.

The hospital stressed that only the one patient was infected, and that there was no risk of other infections.

Furthermore, Tullberg explained that there is a chance the child will not show any symptoms of the illness.

“This particular case is a tragedy and certainly nothing that one should come up against. Small children can be carriers of the infection without being sick and may not have any symptoms. A cure is on the way and probably within a few years,” he told GP.

Meanwhile, the head of the blood donation division at the hospital, Jan Konar, explained that there is always a small risk of such an incident, even though the transfusion was carried out in accordance with the National Board of Health and Welfare’s (Socialstyrelsen) regulations.

“The tests we do are not completely 100 percent accurate. But they are surely 99.999 percent. Statistically you can come up against this kind of thing every seventh or eighth year,” said Konar.

The blood donor is notified of the incident, which has been reported to the National Board in accordance with Sweden's Lex-Maria laws, the informal name for regulations governing the reporting of injuries or incidents in the Swedish health care system.

Hepatitis C is an infectious disease affecting the liver, primarily spread via blood-to-blood contact. There is currently no vaccine available against the virus.

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